The long term objective of this program is to identify certain drugs that reduce the catabolic response to critical illness and ultimately, reduce patient morbidity and mortality. Contemporary metabolic support consisting of nutritional therapy alone fails to prevent marked loss of body protein that accompanies sepsis. This failure is due to the inability of nutritional intervention to increase anabolism sufficiently to overcome the greatly increased catabolism associated with critical illness. Preliminary investigations suggest when drugs that alter those endocrine or immunologic pathways involved in the regulation of protein catabolism and nutrition are used together, their combined effect results in a further decrease in body protein loss in seriously ill patients or animals. However, in many cases, there has not been a reported attempt to replicate these findings nor to determine the optimal dose for these drugs. Four anti-catabolic agents (propranolol, phentolamine, octreotide, and pentoxifylline) with different pharmacologic actions will be studied. The proposed studies will use a parenterally nourished septic animal model to determine the dose response relationship between these drugs and protein metabolism by measuring urinary nitrogen and 3-methylhistidine excretion, and nitrogen balance. Possible adverse consequences of these drugs will be examined by measuring conventional laboratory tests of renal and liver function in addition to determining liver composition. Effective doses of these agents will be used in future work to examine their impact on whole body protein kinetics in addition to studying their effect on the metabolic response of specific organ systems (hepatic, muscle, intestine) and immune system to sepsis. These studies will also serve as the foundation for using selective drugs (e.g., alpha1, adrenergic blocker, etc.) as pharmacologic probes to better understand the possible mechanism for their anti-proteolytic effects. Ultimately, these studies will provide a basis for the logical extension of this work to critically ill patients with sepsis.